Project Summary (Abstract) The progression phenomenon of abnormal tau and amyloid-? (A?) proteins along neuronal circuits is critical to understand the foundations of Alzheimer's disease (AD) pathology. The individual risk to develop late onset AD relates to the biological and genetic profiles that confer susceptibility for abnormal and progressive accumulation of tau and A? in the brain. Recent advances in multi-modal neuroimaging and genetic biomarkers provide new prospects to detect very early stages of AD and to study its network nature and genetic underpinnings. However, a major research challenge in this field has been to integrate and perform comprehensive joint analysis of neuroimaging and genetic data. Thus, there is a critical need for new strategies to detect the spreading pathways and genetic mechanisms of tau-related and A?-related accumulation in the human brain. The combination of detailed descriptions of individual neuroimaging profiles of progression and genetic vulnerability risk will offer enhanced detectability of AD trajectories. This proposal purposes to solve these emerging challenges by focusing on identification of in vivo spreading pathways of tau and A? deposits and their genetic vulnerabilities in a longitudinal sample of elderly participants from the Harvard Aging Brain Study (HABS). In Aim 1, we will develop customized graph theory metrics to detect progression of pathology at the network level in cross-sectional and longitudinal PET images. In Aim2, we will focus on building individualized staging frameworks based on progression and spreading patterns of pathology using PET imaging, and we will correlate staging estimates with clinical and neuropsychological profiles. In Aim 3, we will characterize the genetic brain transcriptome ?assisted by the Allen Human Brain Atlas- that are associated to the HABS neuroimaging spreading profiles. At the end of this proposal, we will be able to detect and identify the early and in vivo molecular imaging and genetic features that confer AD susceptibility in elderly individuals.